[Chronic paracetamol intoxication : under-diagnosed iatrogenic cause of metabolic acidosis with increased anion gap]. / L'intoxication chronique au paracétamol : cause iatrogène sous-diagnostiquée d'acidose métabolique à trou anionique augmenté.

The occurrence of metabolic acidosis with increased anion gap in the context of chronic paracetamol intoxication is an easily treatable clinical situation. Its rapid recognition is essential given its complete reversibility in the event of adequate management by eviction of the toxic agent, in this case paracetamol. It has an unknown cause and therefore potentially under-diagnosed, to be considered in the same way as the other more frequent etiologies. Because of this lack of knowledge, its frequency is probably underestimated considering the widespread consumption of paracetamol in the population.

La survenue d'une acidose métabolique à trou anionique augmenté dans le cadre d'une intoxication chronique au paracétamol est une situation clinique facile à traiter. Sa reconnaissance rapide est essentielle compte tenu de son entière réversibilité en cas de prise en charge adéquate par éviction de l'agent toxique, en l'occurrence le paracétamol. C'est une cause méconnue et de ce fait potentiellement sous-diagnostiquée, à envisager au même titre que les autres étiologies plus fréquentes. Du fait de cette méconnaissance, sa fréquence est probablement sous-estimée au vu de la consommation répandue de paracétamol au sein de la population.

Hepatitis E virus genotype 4 in a pig farm, Italy, 2013.

Zoonotic strains of hepatitis E virus (HEV) in Europe have been reported to belong to genotypes 3 and 4. In 2012 and 2013, 57 pig farms in Northern Italy that had previously resulted seropositive for HEV were surveyed for the presence of the virus, with positive samples subsequently genotyped. Hepatitis E RNA was identified in 17/57 (29·8%) seropositive farms. Phylogenetic analysis demonstrated that distinct subtypes of genotype 3 were circulating in the north-east of Italy; as well, for the first time in the Italian swine population, genotype 4 was identified and attributed to subtype d.

Neuropathic pain following spinal cord injury: what we know about mechanisms, assessment and management.

BACKGROUND: In biology, it is easy to understand how a damaged functional system may generate wrong signals, but why this should happen when the system is disconnected is less clear. For this reason, among other pain syndromes, neuropathic pain (NP) following spinal cord injury (SCI) leaves most questions unanswered. AIMS AND METHODS: Our purpose is to review current knowledge on NP after SCI, focusing on the mechanisms, assessment and management of the syndrome. RESULTS: The mechanisms responsible for NP following SCI are poorly understood: NP is classically considered a "central pain syndrome" but recent evidence from experimental models reveals a possible "peripheral sensitization". Assessment of NP following SCI is well-established: in addition to clinical evaluation and self-reported scales, many neurophysiological, radiological and microscopic investigations may be performed. The management of NP following SCI is very difficult: evidence of effective drugs is lacking and alternative new treatment approaches yield different outcomes. CONCLUSIONS: Recently clinical and instrumental tools have increased our knowledge on NP, suggesting that the discovery of new treatment agents will depend on an explanation of what changes after SCI: future research must point in this direction.

Substrate uptake and protein stability relationship in mammalian histidine decarboxylase.

There is some evidence linking the substrate entrance in the active site of mammalian histidine decarboxylase and an increased stability against proteolytic degradation. In this work, we study the basis of this relationship by means of protein structure network analysis and molecular dynamics simulations. We find that the substrate binding to the active site influences the conformation of a flexible region sensible to proteolytic degradation and observe how formation of the Michaelis-Menten complex increases stability in the conformation of this region.

[Vitamin D deficiency in recently pregnant women]. / La carence en vitamine d chez les femmes enceintes en région liégeoise: un problème méconnu.

We have evaluated the prevalence of the 25-hydroxy vitamin D (25VTD) deficiency in recently pregnant women and new mothers in the area of Liege, Belgium. The study took place in November 2006. Twenty four women who underwent a positive pregnancy test and 65 new mothers were enrolled. The level of 25VTD did not differ between the two groups. Only 12% of the pregnant women and 14% of the new mothers (>12 ng/ml) had an optimal level of 25VTD (>30 ng/ ml). We also observed a severe 25VTD deficiency in 21% of pregnant women and 32% of new mothers. Our results showed that more than 80% of pregnant women and new mothers in the area of Liege presented a deficiency in 25VTD. In Belgium, daily vitamin supplementation of pregnant women is common, but the level of vitamin D3 concentration range from 10 microg (400 UI) to zero microg. In our area, vitamin D production in the skin is not always important enough to achieve optimal levels. Our data show that vitamin D supplementation of pregnant women is not enough and that 25VTD deficiency is not diagnosed in this high-risk population. Children born from deficient mothers will present a higher risk of suffering from bone mineral diseases as well as other pathologies, as type 1 diabetes or neurological disorders. Of course, this insufficiency will also have an impact on mother's bone reserve, but these mothers will also be at higher risk for preeclampsia.

Analogous activation of bovine liver glycogen phosphorylase by AMP and IMP.

The mechanism of activation of glycogen phosphorylase is incompletely understood, although adenosine and inosine nucleotides are known to be important allosteric activators. In this study the activation of glycogen phosphorylases a and b from bovine liver by adenosine 5'-monophosphate (AMP) and inosine 5'-monophosphate (IMP) has been investigated and the results compared with the activation of the muscle isozyme by the same nucleotides. Enzyme activity was determined by spectrophotometric measurement of inorganic phosphate produced in the phosphorylase-catalysed reaction of glycogen synthesis. Liver phosphorylase b binds both nucleotides non-co-operatively (Hill coefficients of 1.0 +/- 0.1), with changes in the maximum velocity to 75 or 80 mumol min-1 mg-1 in the presence of adenosine 5'-monophosphate or inosine 5'-monophosphate, respectively, but no change in the enzyme affinity towards the substrate, glucose-1-phosphate. Binding of glucose-1-phosphate is co-operative and the kinetic data have been fitted with the Monod-Wyman-Changeux model. Liver phosphorylase a has a maximum velocity similar to that of the b form in the presence of nucleotides. Binding of glucose-1-phosphate to the enzyme is non-co-operative (Hill coefficient of 1.0 +/- 0.1) and the affinities in the presence of the nucleotides (Michaelis constants of 28 +/- 0.2 mM or 27 +/- 0.2 mM for adenosine 5'-monophosphate or inosine 5'-monophosphate) are stronger than those of the b form. It is concluded that the activity of bovine liver phosphorylase a and b is similarly influenced by adenosine 5'-monophosphate or inosine 5'-monophosphate. The b form seems to behave like muscle phosphorylase b in response to inosine 5'-phosphate; however, the binding of adenosine 5'-phosphate does not induce the conformational change necessary to activate the liver enzyme, as occurs with the muscle isozyme.

Ro31-8220 inhibits protein kinase C to block the phorbol ester-stimulated release of choline- and ethanolamine-metabolites from C6 glioma cells: p70 S6 kinase and MAPKAP kinase-1beta do not function downstream of PKC in activating PLD.

The use of bisindolylmaleimide derivatives of staurosporine as selective inhibitors of protein kinase C (PKC) is in doubt following the report by Alessi [FEBS Lett. 402 (1997) 121-123] that Ro31-8220 and GF109203X are potent in vitro inhibitors of p70 S6 kinase and mitogen-activated protein kinase-activated protein kinase-1beta, as well as of PKC. Here we show that the phorbol ester-stimulated release of choline- and ethanolamine-metabolites from C6 glioma cells due to phospholipid hydrolysis by phospholipase D (PLD) is not inhibited by rapamycin or PD98059, specific inhibitors respectively of p70 S6 kinase and MAPKK (MEK) and thus of MAPKAP kinase-1beta but is still completely blocked by Ro31-8220. We conclude therefore that p70S6k and MAPKAP kinase-1beta as well as MAPK are not involved in signalling pathways downstream of PKC that regulate phorbol ester-stimulated phospholipid turnover and that the inhibitory action of Ro31-8220 occurs by blocking PKC which regulates at least one pathway to PLD activation. The PI-3 kinase inhibitor, wortmannin, inhibits the phorbol ester-stimulated release of ethanolamine- but not choline-metabolites from C6 cells suggesting that different PLD isoforms regulate the turnover of PtdEth and PtdCho in C6 cells. Both PLD isoforms are activated via PKC but the PtdEth-PLD is also regulated via a wortmannin-sensitive pathway.

Binswanger's disease and normal-pressure hydrocephalus. Clinical and neuropsychological comparison.

We investigated the clinical and cognitive aspects of patients with normal-pressure hydrocephalus and possible Binswanger's disease. We studied 19 patients with normal-pressure hydrocephalus and 19 patients with Binswanger's disease, comparing them with the same number of matched controls. The patients with normal-pressure hydrocephalus had a later age and more frequent gait disturbance at the onset, shorter duration of the illness, rare signs of vascular disturbances, and more frequent severe mental deterioration. Ventricular enlargement may play a role in determining the more rapid and worse clinical course of normal-pressure hydrocephalus.

Carbamazepine and phenytoin. Comparison of cognitive effects in epileptic patients during monotherapy and withdrawal.

We compared the cognitive effects of carbamazepine and phenytoin with neuropsychological tests exploring intelligence, vigilance, attention, memory, and visuomotor performances in 25 epileptics (13 receiving carbamazepine and 12 receiving phenytoin) and 26 matched normal controls. Patients were seizure free for at least two years and taking prolonged monotherapy. We also evaluated the effects of drug withdrawal by retesting patients three months after reduction at half drug dose and three months and one year after complete withdrawal. Our findings suggest that phenytoin affects the cognitive functions more than carbamazepine does, although the negative effects of both drugs are reversible by complete therapy withdrawal.

The 5-HT(3) and nACh ionotropic receptors: a perspective from the computational chemistry point of view.

Recent contributions applying Computational Chemistry to serotonin-3 and nicotinic acetylcholine ionotropic receptors are reviewed. These two receptors constitute a good example for the examination of the computational protocols that have been used to understand how they work. On the one hand, (5-HT(3)R) receptor mapping techniques have been mostly employed in its study and very few examples of receptor fitting have been appeared. On the other hand, (nAChR) has been studied mainly from the receptor fitting point of view, although many contributions using receptor mapping exist. In the first case, antagonists seems to be more important that agonists, so more works are devoted to them. In the second case, agonist development is the main issue. Although far for being complete, in either of the cases we have working pharmacophores as well as 3D models for their binding sites that are ready to be used as a starting guess to design potential drugs. It is noteworthy that the absence of crystallographic structure for these receptors has motivated the interest in their study, constituting an interesting and challenging field. Mutagenesis experiments have allowed the establishment of main amino acids that are essential in the receptor functioning and then, interaction models have been postulated. Although most of the models are speculative in nature, some of them have been proved to be valuable tools for drug design. This scientific field is already open and many areas are still unexplored. Computational tools for treating these issues exist in a wide variety and their rational application would produce the answers to the structure and functioning of these receptors.

Fatal familial insomnia: behavioral and cognitive features.

Fatal familial insomnia (FFI) is a familial prion disease linked to a mutation of the prion protein gene. Neuropsychological investigations in seven patients with FFI belonging to two different families showed that the main behavioral and neuropsychological features are (1) early impairment of attention and vigilance, (2) memory deficits, mainly of the working memory, (3) impairment of temporal ordering of events, and (4) a progressive dream-like state with neuropsychological and behavioral features of a confusional state. Neuropathologic examination of six patients showed prominent neuronal loss and gliosis involving the anterior ventral and mediodorsal thalamic nuclei, with additional cerebral cortical involvement in two cases. Clinicopathologic correlations indicate that FFI is associated with a neuropsychological and behavioral syndrome that is distinct from the cortical and subcortical dementias, and Wernicke-Korsakoff syndrome. These findings offer insights into the function of the thalamic nuclei and challenge the notion of thalamic dementia.

Arylpiperazines with serotonin-3 antagonist activity: a comparative molecular field analysis.

Comparative molecular field analysis (CoMFA) is applied to antagonists of the 5-HT3 receptor. Analysis is done separately on three published sets of arylpiperazines and on a combination of the three sets. d-Tubocurarine, a conformationally restricted 5-HT3 ligand, is used as a template to assist in selecting the conformation of the antagonists for CoMFA alignment. Two forms of the arylpiperazines (neutral and protonated) and three different kinds of calculated charges (Gasteiger-Hückel, AM1, and AM1 with solvation effect included) are compared. Protonated structures give better statistical results than the neutral species. The way in which charges are calculated does not greatly affect the results. In terms of molecular fields, the behavior in each separate set of compounds cannot be extrapolated to the combined set of 47 compounds. The average value of r2cv from PLS cross-validation on the combined set is 0.70 and varies between 0.56 and 0.80 depending on the orientation of the molecules in the coordinate system. The CoMFA model is tested on four compounds not in the training set: quipazine, N-methylquipazine, 4-phenyl-N-methylquipazine, and KB-6933. Mean agreement of experimental and predicted pKi values of the antagonists is 0.7 log unit. Novel structural modifications are interpreted by the CoMFA model.

The effect of converting from pravastatin to simvastatin on the pharmacodynamics of warfarin.

Forty-six adult patients maintained on warfarin therapy were converted from pravastatin to simvastatin. Mean international normalized ratio (INR) significantly increased from 2.42 to 2.74, p = 0.002. Although warfarin doses were reduced in 7 patients and increased in 4 patients following the post-conversion INR measurements, the pre- and postconversion median weekly warfarin dose of all 46 patients did not differ significantly. The number of patients with an INR > 3.0 increased significantly from 6 to 16 following the conversion. There was no report of unusual episodes of bleeding. The results indicate that antihyperlipidemic therapy can be changed safely from pravastatin to simvastatin in patients who are taking warfarin concomitantly. Additional anticoagulation monitoring is not necessary in institutions where patients are followed in formal anticoagulation clinics.

Drug-induced psychosis and depression in the elderly.

This article discusses drug-induced psychosis and depression in the elderly population. Selected reports with particular emphasis on the geriatric population are evaluated with histamine blockers, antiparkinson, anti-inflammatory, antituberculosis, antineoplastic, antidepressant, anticonvulsant, cardiac, antihypertensive, and steroid drugs. Particular emphasis is placed on possible mechanisms of these side effects and factors contributing to increased incidence in the elderly population. In review, the clinician is advised to use special caution when prescribing these agents in the elderly considering increasing patterns of drug-induced psychosis and depression.

Retrospective and prospective analyses of the treatment of overanticoagulated patients.

STUDY OBJECTIVE: To compare withholding warfarin therapy with low-dose (2.5 mg) oral vitamin K therapy in excessively anticoagulated patients without bleeding complications. DESIGN: Prospective and retrospective studies. SETTING: Anticoagulation clinic at a Veterans Affairs institution. PATIENTS: Twenty-eight men were matched according to initial international normalized ratio (INR) and INR goal ranges. INTERVENTIONS: The retrospective arm of the study consisted of chart reviews of overanticoagulated patients whose warfarin doses were held until therapeutic INR values were reached. The prospective arm included overanticoagulated patients who were administered a single 2.5-mg dose of oral vitamin K. MEASUREMENTS AND MAIN RESULTS: Mean days to therapeutic INR values were 2.3+/-0.6 and 1.4+/-0.6 (p=0.001), and mean reduction in INR 1 day after treatment intervention was 1.32+/-0.79 and 3.46+/-1.31 (p<001) U for the withholding and vitamin K groups, respectively. CONCLUSION: Compared with withholding the warfarin dose, administration of 2.5 mg of oral vitamin K to excessively anticoagulated patients receiving warfarin significantly reduced the time required to reach a therapeutic INR as well as final INR.

"Fatal familial insomnia": neuropsychological study of a disease with thalamic degeneration.

Fatal Familial Insomnia (FFI) is an inherited disease characterized clinically by sleep, autonomic and motor disturbances and pathologically by marked atrophy of the anterior and dorsomedial nuclei of the thalamus. The neuropsychological study of three cases of FFI showed: (1) a progressive disturbance of attention and vigilance, (2) a memory deficit with lability of mnesic traces and difficulty in manipulation and ordering of events, suggesting an alteration of working memory and (3) a deficit of frontal abilities with impairment in planning and prevision of events but preservation of general intelligence.

Cognitive effects of valproate.

The effects of valproate on cognition are usually considered to be minimal, but few formal neuropsychological studies are available. We studied the psychomotor performances of 20 seizure-free epileptics during fixed valproate monotherapy and after its withdrawal. Our findings suggest some adverse effects of valproate which appear to be completely reversible after withdrawal.

Ligand-receptor interaction at the neural nicotinic acetylcholine binding site: a theoretical model.

Recent mutagenesis experiments have identified some of the functional amino acids that are essential in the interaction of nicotinic agents with the binding site of the neural nicotinic acetylcholine receptor (nAChR). Although this receptor is one of the best studied and characterized the lack of detailed experimental information regarding its quaternary structure has turned it into a challenge for computational chemistry. We have previously reported [J. Comput. Aided Mol. Design 13 (1999) 57-68] a computational protocol based on molecular mechanics and molecular dynamics (MD) where SER82, ASP83, TRP86, ASP89, TYR93, TYR190, TYR198 and ARG209 were placed around selected agonists and antagonists aided by stereoelectronic criteria. Explicit water molecules were used with the double goal of simulating aqueous environment and keeping the system from falling apart. The protocol was stable enough to allow the ligands to evolve to their thermodynamically most probable structure while maintaining the key interactions. In this communication we use the average model for the agonists (one average structure for each agonist) to calculate quantum mechanically the interactions of the binding site with one neurotransmitter acetylcholine (ACh, 1), as well as with two of the most potent agonists described so far [nicotine (2) and epibatidine (3)] and the modeled binding site. A wide variety of methods as well as basis sets were used in order to rationalise the best way to treat the problem. In this limited set of compounds, a good correlation between total interaction energies and biological affinity is observed.

Superimposition-based protocol as a tool for determining bioactive conformations. I. Application to ligands of the glycinergic receptor (GlyR).

The natural templates (NT) approach, which is a superimposition-based protocol that has been successfully employed in several studies, is here applied to ligands of the glycine ligand-gated ion channel receptor. Bioactive conformations for glycine and its analogs were obtained using strychnine (a natural and specific competitive antagonist) as template. Experimental evidence was used to guide the superimposition protocol. Three essential regions have been defined in strychnine's structure that serve as a pharmacophore for agonist and antagonist activities. Reasonable alignments of known ligands were found in the majority of the cases. Molecular mechanics (i.e., conformational searches for the relatively flexible ligands) and molecular dynamics (for relatively rigid ligands such as strychnine and 5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol) were used to assess the energetic accessibility of the proposed bioactive conformations.

Superimposition-based protocol as a tool for determining bioactive conformations. II. Application to the GABA(A) receptor.

The natural templates (NT) superimposition method is used to determine the pharmacophoric requirements of the A subtype of the gamma-aminobutyric acid (GABA) receptor. Bioactive conformations for antagonists and agonists are found by superimposing them on a relatively rigid alkaloid bicuculline, which itself is a competitive antagonist at this ligand-gated ion channel receptor. As has been usual in the application of this modeling method, consideration of available experimental data is the cornerstone for obtaining realistic models. The identification of two substructural fragments of bicuculline permitted classification of the ligands. Analysis of the antagonists and agonists with respect to the two substructural fragments revealed two bioactive conformations of the highly flexible GABA molecule, one of which is extended with the nonhydrogenic atoms roughly coplanar torsional angles of -37 and -179 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively. The second bioactive compound is clearly non planar (torsional angles of -81 and -109 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively).